Communication between small cytosolic dsDNA and autophagy inhibits CGAS (cyclic GMP-AMP synthase) activation

ABSTRACTThe CGAS (cyclic GMP-AMP synthase)-STING1 (stimulator of interferon response cGAMP interactor 1) pathway is an important innate immune pathway that induces proinflammatory cytokine production following stimulation with dsDNA > 45 bp. We recently identified a class of ~ 20–40 bp small cytosolic dsDNA (scDNA) that blocks CGAS-STING1 activation. In this punctum, we discuss the mechanism underlying the inhibition of CGAS-STING1 activation via scDNA. scDNA binds to CGAS but cannot activate its enzymatic activity. It competes with dsDNA > 45 bp for binding with CGAS to inhibit CGAS-STING1 activation. Moreover, scDNA activates macroautophagy/autophagy and induces the autophagic degradation of STING1 and long dsDNA. Autophagy then increases scDNA levels, driving a feedback loop that accelerates the degradation of STING1 and long cytosolic dsDNA. These findings reveal that mutual communication between scDNA and autophagy inhibits CGAS-STING1 activation following stimulation with dsDNA > 45 bp.KEYWORDS: DNA damageinterferon-βPIK3C3small cytosolic double-stranded DNASTING1 Disclosure statementNo potential conflict of interest was reported by the authors.Additional informationFundingThis work was supported by the National Natural Science Foundation of China (grant nos. 81972648, 82172915, and 81773011) and the Chongqing Medical University Program for Youth Innovation in Future Medicine (grant no. W0084).